PROJECT SUMMARY Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Its lead agent MTX-211 was discovered in collaboration with the Leopold laboratory at University of Michigan. The overall objective of this project is to expediently advance MTX- 211 into development for the treatment of KRAS mutant colorectal cancer (CRC). Every year >130,000 new patients are diagnosed with colorectal cancer. At the time of diagnosis, approximately 20% of these patients present with metastatic disease. Currently, there are no approved treatments for metastatic CRC patients with activating mutations in KRAS. MTX-211 is a first-in-class highly selective dual inhibitor of PI3K and EGFR kinases, designed to attack KRAS oncogenic signaling using two orthogonal mechanisms. As such, it embodies a combination approach in a single molecule. Phase I aims focused on optimizing the synthetic process to scale-up production of MTX-211 and conducting a pilot mouse trial of primary xenograft models established from six different patients diagnosed with KRAS mutant CRC. All milestones were achieved providing preclinical proof-of-concept for pursuit of a clinical development path for MTX-211 that specifically targets the KRAS mutant CRC population. In Phase II, we propose to test a broader panel of KRAS mutant CRC models in an expanded efficacy trial that incorporates molecular profiling to identify prognostic markers that correlate with therapeutic outcome. At the same time, we propose to carry out early safety studies to further de-risk MTX-211 and strengthen the case for moving forward to future IND-enabling toxicology studies.